Antimalarial Activity of 4-Metoxychalcones: Docking Studies as Falcipain/Plasmepsin Inhibitors, ADMET and Lipophilic Efficiency Analysis to Identify a Putative Oral Lead Candidate

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Abstract

Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a– i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC ₅₀ values ranging from 1.96 µM to 10.99 µM, with moderate or low cytotoxicity against the HeLa cell line. The compound 1a (IC ₅₀ = 2.06 µM) had the best selectivity index (9.0). All the sulfonamide 4-metychalcone derivatives synthesized had cLogP values between 2 and 5 (mean value 3.79) and molecular weights (MWs) below 500. The substitution of the pyrrolidine group in 1i by a morpholine group in 1a reduced the cLogP value from 3.05 in compound 1i to 2.34 in compound 1a. Indeed, compound 1a had the highest LipE value. The binding free energy of compound 1a showed it to be the most optimal chalcone derivative for plasmepsin-2 (−7.3 Kcal/mol). The physicochemical properties and LipE analysis of the dataset allowed us to establish that compound 1a is the highest quality compound of the series and a potential oral lead candidate.

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Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements

James J. P. Stewart (2007)

Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol−1. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol−1. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol−1. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries. Figure Calculated structure of the complex ion [Ta6Cl12]2+ (footnote): Reference value in parenthesis Electronic supplementary material The online version of this article (doi:10.1007/s00894-007-0233-4) contains supplementary material, which is available to authorized users.

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Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study

Aung Pyae Phyo, Aung Phyo, Standwell Nkhoma … (2012)

Summary Background Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border. Methods In malaria clinics located along the northwestern border of Thailand, we measured six hourly parasite counts in patients with uncomplicated hyperparasitaemic falciparum malaria (≥4% infected red blood cells) who had been given various oral artesunate-containing regimens since 2001. Parasite clearance half-lives were estimated and parasites were genotyped for 93 single nucleotide polymorphisms. Findings 3202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2·6 h (95% CI 2·5–2·7) in 2001, to 3·7 h (3·6–3·8) in 2010, compared with a mean of 5·5 h (5·2–5·9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6·2 h) increased from 0·6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010. Interpretation Genetically determined artemisinin resistance in P falciparum emerged along the Thailand–Myanmar border at least 8 years ago and has since increased substantially. At this rate of increase, resistance will reach rates reported in western Cambodia in 2–6 years. Funding The Wellcome Trust and National Institutes of Health.

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The influence of drug-like concepts on decision-making in medicinal chemistry.

Paul D Leeson, Brian Springthorpe (2007)

The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.

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Author and article information

Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 10 December 2013

Publication date Collection: December 2013

Volume: 18

Issue: 12

Pages: 15276-15287

Affiliations

[1 ]Centro de Ciências da Saúde-UFSJ/Campus Centro-Oeste, CEP 35501-296, Divinópolis, MG, Brazil

[2 ]Instituto de Ciências da Saúde-UFMT/Campus Sinop, CEP 78557-267, Sinop, MT, Brazil

[3 ]Departmento de Ciências Farmacêuticas-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, Brazil

[4 ]Departmento de Química-UFSC/Campus Universitário Trindade, CEP 88040-900, Florianópolis, SC, Brazil

Author notes

[* ]Authors to whom correspondence should be addressed; E-Mail: viana@ 123456ufsj.edu.br (G.H.R.V.); varotti@ 123456ufsj.edu.br (F.P.V.); Tel.: +55-37-3221-1610 (G.H.R.V. & F.P.V.); Fax: +55-37-3221-1614 (G.H.R.V. & F.P.V.).

Article

Publisher ID: molecules-18-15276

DOI: 10.3390/molecules181215276

PMC ID: 6269736

PubMed ID: 24335577

SO-VID: 1be015de-1f61-4724-83e6-e434419a2b91

License:

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

History

Date received : 20 September 2013

Date revision received : 23 November 2013

Date accepted : 30 November 2013

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